State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
J Med Chem. 2022 Aug 25;65(16):11187-11213. doi: 10.1021/acs.jmedchem.2c00681. Epub 2022 Aug 4.
Most vascular disrupting agents (VDAs) fail to prevent the regrowth of blood vessels at the edge of tumors, causing tumor rebound and relapse. Herein, a series of novel multifunctional vascular disrupting agents (VDAs) capable of inhibiting microtubule polymerization and histone deacetylases (HDACs) were designed and synthesized using the tubulin polymerization inhibitor as the lead compound. Among them, compound exhibited the most potent antiproliferative activity (IC = 18-30 nM) against a panel of cancer cell lines. As expected, inhibited tubulin assembly and increased the acetylation level of HDAC substrate proteins in HepG2 cells. Further antitumor assay displayed that effectively inhibited tumor growth with no apparent toxicity. More importantly, disrupted both the internal and peripheral tumor vasculatures, which contributed to the persistent tumor inhibitory effects after drug withdrawal. Altogether, deserves to be further investigated for the new approach to clinical cancer therapy.
大多数血管破坏剂（VDAs）未能防止肿瘤边缘血管的再生，导致肿瘤反弹和复发。在此，设计并合成了一系列新型多功能血管破坏剂（VDAs），它们能够抑制微管聚合和组蛋白去乙酰化酶（HDACs），使用微管聚合抑制剂 作为先导化合物。其中，化合物 对一组癌细胞系表现出最强的抗增殖活性（IC = 18-30 nM）。正如预期的那样， 抑制微管组装并增加 HepG2 细胞中 HDAC 底物蛋白的乙酰化水平。进一步的抗肿瘤测定显示， 有效抑制肿瘤生长，且无明显毒性。更重要的是， 破坏了内部和外围的肿瘤脉管系统，这有助于在停药后持续抑制肿瘤。总的来说， 值得进一步研究，以探索治疗癌症的新方法。
